Arthritis is currently one of the most frequent diseases of the human population. Among approximately one hundred different types of arthritis, osteoarthritis (OA) belongs to those which management requires the most financial investments and thus imposes a major burden for the economy [L. S. Simon, Osteoarthritis 25 (1999) 345].
In OA the synovial fluid becomes more abundant and less viscous while the concentration of synovial hyaluronan (HA) as well as its molecular weight decrease. [J. G. Peyron, J. Rheum. 20, Suppl. 39 (1993) 10]. These changes are kept co-accountable for the subsequent accelerated degradation of the cartilage. Intra-articular (injection) administration of the high-molecular-weight HA to the patients (this therapy is currently called “viscosupplementation”) is described as an effective procedure in the treatment of traumatized arthritic joints [T. Kikuchi et al., Osteoarthritis and Cartilage 4 (1996) 99].
The average molecular weight of synovial HA of healthy humans lies in the range (1.6-10.9)×106 Da; while its concentration equals 2-3 mg/ml [E. A. Balazs et al., Arthritis Rheum. 10 (1967) 357]. Molecular weight values of commercially available HA preparations obtained from various (natural) sources such as e.g. bacteria Streptococcus zooepidemicus or Streptococcus equii, rooster combs, etc., vary in the range from hundreds of thousands to ca. 1-2 million Da (FIG. 1). High-molecular-weight HA binds up to 1000 times more water than is its own mass and forms pseudoplastic, elastoviscous solutions, that behave as soft gels that reveal so-called shear-dependent viscosity and frequency-dependent elasticity [N. E. Larsen and E. A. Balazs, Adv. Drug Delivery Rev. 7 (1991) 279]. At the low magnitude of the shear tension, solutions of high-molecular-weight HA reveal high viscosity and low elasticity; while at the increasing values of shear tension the solutions become more elastic [L. S. Simon, Osteoarthritis 25 (1999) 345]. Such non-Newtonian behavior of synovial fluid is essential for the lubrication of joints during the (fast) movement. The cartilage surface is covered by a thin film of SF that smoothens (fine) unevenness of the articular structure. Deficiency of this layer leads to increased friction coefficient between the moving parts of the joint which results in strong pain [M. Nishimura et al., Biochim. Biophys. Acta 1380 (1998) 1]. Ultrapure (ready for injection application) preparations of the elastoviscous solutions of the hyaluronan sodium salt (HEALON®; Pharmacia, Uppsala, Sweden), obtained from the rooster combs, have found extended application especially in ophthalmology (viscosurgery) [A. Nimrod et al, J. Ocular Pharmacol. 8 (1992) 161], as well as in rheumatology (viscosupplementation) [J. G. Peyron, J. Rheumatology 20, Suppl. 39, (1993) 10; T. Kikuchi et al, Osteoarthritis and Cartilage 4 (1996) 99].
Recently another preparation for the intra-articular administration to OA patients was approved in the USA and some other countries. This new product containing high-molecular-weight HA originating from the rooster combs, named HYLAN® (Biomatrix Inc., Ridgefield, N.J., USA) included additionally cross-linked HA [L. S. Simon, Osteoarthritis 25 (1999) 345]. The rationale (of this innovation) is the fact that the period of time during which the intra-articularly deposited hyaluronan exerts its activity is relatively short. The biological half-life of HA after its intra-articular application into the rabbit's knee joint was ˜13 hours [T. J. Brown et al, Exp. Physiol. 76 (1991) 125]. (The turnover of endogenous hyaluronan in the joints lasts 12-48 hours [J. Drobnik, Adv. Drug Delivery Rev. 7 (1991) 295].) The water-soluble HYLAN®s with ultra-high molecular weight (on average around 6×106 Da) that were prepared by chemical cross-linking of HA with formaldehyde reveal a significantly longer biological half-life period [L. S. Simon, Osteoarthritis 25 (1999) 345]. HYLAN®s prepared in this way, i.e. using a chemical cross-linking represent the most effective viscosupplementation (bio)materials. In the other (water-insoluble) HYLAN® preparations (gels, membranes, microparticles) HA is cross-linked through the introduced vinylsulfone groups with resulting formation of the “infinite” poly(macro)molecular network [N. E. Larsen and E. A. Balazs, Adv. Drug Delivery Rev. 7 (1991) 279].
However summarizing all literature data on the pre-clinical and clinical trials that involved injections of HYLAN® solutions [N. E. Larsen and E. A. Balazs, Adv. Drug Delivery Rev. 7 (1991) 279; S. Al-Assaf et al, Radiat. Phys. Chem. 46 (1995) 207; M. Wobig et al., Clin. Ther. 20 (1998) 410; L. S. Simon, Osteoarthritis 25 (1999) 345] one can come to a conclusion that along with their remarkable useful properties such as biocompatibility, (bio)degradability, (complete) resorption, non-immunogenicity, very low and rare pyrogenicity, their obvious drawback is a very high viscosity. Due to the fact that intra-articularly (through injection) administered ultra-high-molecular-weight hyaluronans (HYLAN®s) are enormously viscous pseudoplastic gels, their penetrability into the narrow clefts/slits of the damaged articular structure is (obviously) largely impaired.